Piperidyl bis(parachlorophenoxy) acetates

ABSTRACT

THE COMPOUNDS ARE OF THE CLASS OF BASIC ESTERS OF BIS(P-CHLOROPHENOXY)ACETIC ACID, E.G., BIS-(P-CHLOROPHENOXY) ACETIC ACID 1-METHYL-4-PIPERIDYL ESTER, WHICH ARE USEFUL AS HYPOCHOLESTEREMIC/HYPOLIPEMIC AGENTS.

United States Patent C US. Cl. 260-2943 7 Claims ABSTRACT OF THEDISCLOSURE The compounds are of the class of basic esters of bis-(p-chlorophenoxy)acetic acid, e.g., bis-(p-chlorophenoxy) acetic acid1-methyl-4-piperidyl ester, which are useful ashypocholesteremic/hypolipemic agents.

This is a continuation-in-part of my copending application Ser. No.598,970, filed Dec. 5, 1966, which in turn is a continuation-in-part ofmy copending application Ser. No. 568,759, filed July 29, 1966, which inturn is a continuation-in-part of my copending application Ser. No.549,475, filed May 12, 1966, all three now abandoned.

This invention pertains to derivatives of acetic acid. In particular,the invention is directed to basic esters of bis-(p-chlorophenoxy)acetic acid. The basic esters of the present inventionmay be represented structurally as follows:

CHCOOR wherein R represents -(CHR),,R

(the point of attachment being at either the 2- or 3-positions) (thepoint of attachment being at either the 2-, 3- or 4-p0sitions) 3,575,988Patented Apr. 20, 1971 (the point of attachment being at either the 2-or 3-positions) (the point of attachment being at either the 2- or3-positions);

(the point of attachment being at either the 2- or 3-positions) (thepoint of attachment being at either the 2-, 3- or 4-positions) or2-dimethylamino-2-methy1 propyl; R represents (the point of attachmentbeing at either the 2- or 3-positions) (the point of attachment being ateither the 2-, 3- or 4-positions) (the point of attachment being ateither 2 or 3-positions) (the point of attachment being at either the 2-or 3-positions);

(the point of attachment being at either the 2- or 3-positions) nrepresents a whole number of from 1 to 4, inclusive;

each R, independently, represents hydrogen or lower alkyl, preferablycontaining from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl andhutyl;

n represents 2, 3 or 4;

R represents lower alkyl, preferably containing from 1 to 4 carbonatoms, e.g., methyl, ethyl, propyl and butyl; propargyl; phenyl;halophenyl, the halo substituent preferably being bromo or chloro; orphenyl(lovver) alkyl, the lower alkyl substituent preferably containingfrom 1 to 4 carbon atoms, e.g., benzyl and phenethyl;

R represents hydrogen; halo, preferably bromo or chloro;

or lower alkyl, preferably containing from 1 to 4 carbon atoms, e.g.,methyl, ethyl, propyl and butyl;

R represents hydrogen; lower alkyl, preferably containing from 1 to 4carbon atoms, e.g., methyl, ethyl, propyl and butyl; cycloalkylcontaining from 5 to 7 ring carbon atoms, e.g., cyclopentyl, cyclohexyland cycloheptyl; phenyl; phenyl(lower)alkyl, the lower alkyl substituentpreferably containing from 1 to 4 carbon atoms, e.g., benzyl andphenethyl; l-naphthyl; or Z-naphthyl; and

R represents lower alkyl, preferably containing from 1 to 4 carbonatoms, e.g,, methyl, ethyl, propyl and butyl; cycloalkyl containing from5 to 7 ring carbon atoms, e.g., cyclopentyl, cyclohexyl and cycloheptyl;phenyl; or phenyl(lower)alkyl, the lower alkyl substituent preferablycontaining from 1 to 4 carbon atoms, e.g., benzyl and phenethyl;provided that when R is hydrogen R is phenyl.

As illustrative of the substituents represented by R there may bementioned the following:

l-lower alkyl-4-piperidyl, e.g., l-methyl-4-piperidyl andl-ethyl-4-piperidyl; l-lower alkyl-3 piperidyl, e.g., l-

methyl-3-piperidyl and l-ethyl-S-piperidyl; l-lower alkyl- 2-piperidyl,e.g., l-methyl-Z-piperidyl and l-ethyl-Z-piperidyl;1-phenyl-4-piperidyl; 1-phenyl-3-piperidyl; l-phenyl- 2-piperidyl;l-benzyl-4-piperidyl; l-benzyl-3-piperidyl; l-

phenethyl-4-piperidyl; 1-phenethyl-3-piperidyl; l-propargyl-4-piperidyl;l-propargyl 3 piperidyl; l-[B-(p-chlorophenoxy)ethyl]-4-poperidyl;3-quinuclidinyl; Z-quinuclidinyl, fl-pyrrolidinoethyl;-pyrrolidinopropyl; ,G-piperidinoethyl; 'y-piperidinopropyl;[3-morpholinoethyl; 'y-morpholinopropyl; ,B-dimethylaminoethyl;'ydiethylaminopropyl; ,B-anilinoethyl; -anilinopropyl;8-(N-methylanilino)ethyl; ,B-(I-lower alkyl-Z-pyrrolidinyl)ethyl, e.g.,B-(l-methyl-Z- pyrrolidinyl) ethyl; l-lower alkyl-Z-pyrrolidinyl)propyl, e.g., 'y-( l-methyl-Z-pyrrolidinyl)propyl;fl-(1-phenyl-3-pyrrolidinyl)ethyl; B (l-phenyl-Z-pyrrolidinyl)ethyl;8-(1- benzyl-3-pyrrolidinyl) ethyl; l-benzyl-2-pyrrolidinyl) ethyl; ;9-(l-phenethyl-3-pyrrolidinyl)ethyl; ;8-( l-phenethyl- 2-pyrrolidinylethyl; fil-prop argyl-3-pyrrolidinyl ethyl; B-(l propargyl2-pyrrolidinyl)ethyl; and fi-[l-[fl-(pchlorophenoxy ethyl]-3-pyrrolidinyl1 ethyl.

The above-noted compounds can be prepared by a one step process whichinvolves the reaction of either an alkyl ester of bis-(p-chlorophenoxy)acetic acid or a dialkyl ester of bis-(p-chlorophenoxy)malonic acid withan appropriate alcohol. Alternatively, the compounds may be prepared byconverting bis-(p-chlorophenoxy)acetic acid to its corresponding acidhalide and reacting the latter with an appropriate alcohol oralcoholate. These processes are illustrated by the following reactionscheme:

/CHCOOB." C-(COOR)2 Cl- 0 Cl 0 II -I- III It OH CHGOOR \EOH (oraleoholate) CHCOOH CHCOX R is as previously defined;

The reaction of the monoor di-alkyl ester II or III) with theappropriate alcohol is carried out in a suitable inert organic solvent,e.g. benzene, toluene and Xylene, and in the presence of an alkali metalalkoxide, such as sodium methoxide or sodium ethoxide. The reaction isconveniently effected at an elevated temperature, preferably the refluxtemperature of the system. The desired product is readily recovered inconventional manner.

In the alternative process, bis-(p-chlorophenoxy)acetic acid (IV) isconverted to the corresponding acid halide (V) by reaction with thionylchloride or other suitable reagent commonly used for this purpose, e.g.,thionyl bromide, phosphorus pentachloride and phosphorus pentabromide.The reaction is conveniently carried out in a suitable inert organicsolvent and at room temperature (20 C.) or elevated temperatures up toreflux temperature of the system. However, the use of a solvent is notnecessary since an excess of the halide reagent can be employed for thispurpose. It is generally preferred to carry out the reaction in thepresence of a catalytic amount of dimethylformarnide. The reaction ofthe thus-obtained acid halide with the appropriate alcohol or alcoholateis conveniently effected in a suitable inert organic solvent, e.g.benzene, toluene, chloroform and diethyl ether, and at room temperature(20 C.) or below. The reaction, if desired, can be carried out atelevated temperatures; however, in such instances, external coolingshould be provided since the reaction is highly exothermic. Preferablythe reaction is carried out at a temperature of from about 10 to abotuC. Where the free alcohol is employed it is desirable to provide a meansfor taking up the liberated hydrogen halide. This can be accomplished byemploying an excess of the alcohol or by carrying out the reaction inthe presence of an alkali metal carbonate, e.g., potassium carbonate, orsuitable inert base, e.g. pyridine. Where an alcoholate is used, thealkali metal salts, particularly the sodium and potassium salts, arepreferred. The desired product thus obtained is readily recovered inconventional manner.

The monoand di-alkyl esters (II and III) employed as starting materialsare readily prepared by reacting pchloro-sodium phenolate (prepared fromp-chlorophenol and sodium hydride) with a lower alkyl dichloroacetate ordi-(lower) alkyl dibromornalonate, respectively. The reaction is readilycarried out in a suitable inert organic solvent, e.g.,dimethylacetamide, diethylacetamide and dimethylformamide, and at roomtemperature or elevated temperature (which should not exceed about 80 C.when it is desired to prepare the esters of Formula III).

The bis-(p-chlorophenoxy)acetic acid (IV), employed as the startingmaterial for the alternative process described above, can be readilyprepared in conventional manner from either the monoor di-alkyl ester(II or III) by reacting the same in an aqueous, inert organic solvent,with a strong base, at room temperatures. The base is preferably onewhich will yield a water-soluble salt of the desired acid, e.g., sodiumhydroxide and potassium hydroxide. The acid then is obtained by simplytreating the thus-obtained salt With a mineral acid, such ashydrochloric acid, in conventional manner. The acid (IV) can also beprepared by decarboxylating the free malonic acid (III, R"=H) inconventional manner.

Many of the alcohols employed as starting materials are known and can beprepared as described in the literature. Such others which may not bespecifically known can be prepared from available materials in analogousmanner. The alcoholates can be prepared from the corresponding alcoholsin conventional manner.

Certain of the compounds of Formula I have asymmetric centers andtherefore exist as optical isomers. The respective isomers can bereadily separated by conventional techniques or they can be selectivelyprepared employing the desired isomeric form of the alcohol reactant andaccordingly are included within the scope of this invention.

Representative compounds which can be made in the manner set forth aboveand are included within the scope of this invention are set forth intabular form below. For convenience only, the compounds are identifiedby setting forth the significance of the ester moiety represented by Rin structural Formula I. However, it is to be understood that thedesignation of the compounds in this manner is merely in lieu of settingforth the chemical name thereof.

Compound: R

Compound Compound: R C0mp0nnd Compound The compounds of the presentinvention (Formula I) are useful because they possess pharmacologicalactivity in animals. In particular, the compounds possess markedhypocholesteremic activity and can be used ashypocholestermic/hypolipemic agents.

'For such usage, the compounds may be admixed with conventionalpharmaceutical carriers, and other adjuvants, if necessary, andadministered orally in such forms as tablets, elixirs, suspensions orsolutions. Furthermore the compounds may be similarly administered inthe form of their non-toxic pharmaceutically acceptable acid addition orquaternary salts. Such salts do not materially differ from the free basein their pharmacological effects andare included within the scope of theinvention. The acid addition salts are readily prepared by reacting thebase with pharmacologically acceptable acids in conventional manner.Representative of such salts are the mineral acid salts such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts such as the benzoate, acetate, maleate,p-toluenesulfonate, benzenesulfonate and the like. Similarly, thequaternary salts are prepared by reacting the base with pharmacologically acceptable quaternizing agents in conventional manner.Exemplary of the quaternary salts are those derived from commonquaternizing agents such as straight-chain lower alkyl halides whereinthe lower alkyl group preferably contains from 1 to 4 carbon atoms andthe halide substituent is either chloride, bromide or iodide, e.g.,methyl bromide, methyl chloride, ethyl bromide, methyl iodide and ethyliodide, and straight-chain di- (lower) alkyl sulfates, e.g., dimethylsulfate.

For the above-mentioned use, the dosage administered will, of course,vary depending on the compound employed. However, in general,satisfactory results are obtained when administered at a daily dosage offrom about 4 milligrams to about 30 milligrams per kilogram of animalbody weight, preferably given in divided doses, 2 to 4 times a day, orin sustainted release form. For most mammals the administration of fromabout 0.25 gram to about 2 grams of the compound in divided doses offrom about 62.5 milligrams to about 1000 milligrams 2 to 4 times a day,is adequate for the treatment of hypercholesteremia/hyperlipemia. Arepresentative formulation suitable for oral administration is a tablet(prepared by standard tabletting techniques) and containing, by weight,50 parts of bis-(p-c'hlorophenoxy)acetic acid 1-methyl-4- piperidylester (as the free base), 2 parts of tragacanth, 39.5 parts of lactose,5 parts of corn starch, 3 parts of talcum and 0.5 part of magnesiumstearate.

As noted hereinabove certain of the compounds of Formula I exist asoptical isomers. In some instances, enhanced activity or otherbeneficial attribute may be found with respect to a particular isomerand in such instances administration of such isomer may be preferred.

The following examples show representative compounds contemplated by thepresent invention and the manner in which said compounds are made.However, it is to be understood that the examples are intended for thepurpose of illustration only and are not intended as in any way limitingthe scope of the invention which is defined in the appended claims.

EXAMPLE 1 Bis-(p-chlorophenoxy)acetic acid fi-piperidinoethyl ester StepA. Preparation of bis-(p-chlorophenoxy)acetic acid methyl ester: Asolution of 25.6 grams of 4chlorophenol in 200 ml. of dimethylacetamideis slowly added to a stirring slurry of 9.5 grams of sodium hydride (56%in mineral oil) in 250 ml. of dimethylacetamide and the mixture stirredat 20 C. for one hour.

To the resulting clear solution is added 14.3 grams ofmethyl-dichloro-acetate in 200 ml. of dimethylacetamide and a catalyticamount of potassium iodide. The reaction mixture is stirred at 20 C. for17 hours and then poured over 1 liter of ice water. The mixture is thenextracted with isopropyl ether. The separated ether layer is extractedwith cold 1 N sodium hydroxide and the organic phase separated, driedover magnesium sulfate and evaporated to obtain a brown oil whichcrystallizes upon standing. Recrystallization of the resulting productfrom methanol yields bis- (p-chlorophenoxy) acetic acid methyl ester,M.P. 54.5-55.5 C.

Step B. Preparation of bis-(p-chlorophenoxy)acetic acidB-piperidinoethyl ester: Bis-(p-chlorophenoxy)acetic acid methyl ester,10 grams, is mixed with 10 grams of B- hydroxyethylpiperidine, 50 mg. ofsodium methoxide and 10 ml. of toluene. The resulting mixture is thenslowly heated to distill very slowly through a Vigreux column. When thetemperature at the distilling head reaches C., the reaction mixture iscooled to 65 C. and then evaporated on a rotary evaporator employing 12mm. vacuum and maintaining the temperature between 65-70 C. The crudeproduct thus obtained is treated with an excess of a 20% aqueoussolution of tartaric acid to yield the tartrate salt ofbis-(p-chlorophenoxy)acetic acid [i-piperidinothyl ester. The free baseis obtained by treating the washed tartrate salt with 2 N sodiumhydroxide and extracting the base with dichloromethane.

To obtain the hydrochloride salt, the dichloromethane extract is driedover magnesium sulfate, the solvent evaporated and the residueneutralized with an isopropanolic solution of hydrogen chloride (10%hydrogen chloride gas in isopropyl alcohol). The thus-obtainedhydrochloride salt is recrystallized from acetone/diethyl ether to yieldhygroscopic bis-(p-chlorophenoxy)acetic acid piperidinoethyl esterhydrochloride, decomposition point 80 C.

EXAMPLE 2 Bis (p chlorophenoxy)acetic acid 1-rnethyl-4-piperidyl ester Amixture of 14.4 g. (0.151 mole) of 1-methyl-4-hydroxy piperidine in '70ml. of toluene is cooled to about 5 C. in an ice-salt bath. To thecooled mixture is then added dropwise with stirring a solution of 25 g.(0.076 mole) of bis-(p-chlorophenoxy)acetyl chloride in 50 ml. oftoluene, While maintaining the temperature of the reaction mixturebetween -5 and 0 C. with external cooling. After the addition iscompleted, the mixture is stirred for an additional minutes and then 50ml. of ice water and 75 ml. of an aqueous sodium bicarbonate solutionare added and the phases separated. The organic phase is then washedthree times with 100 ml. (each) of water, then dried over magnesiumsulfate and evaporated. The residue thus obtained is recrystallized fromethanol, using some charcoal to remove colored by-products, to obtainbis-(pchlorophenoxy)acetic acid 1-methyl-4-piperidyl ester, M.P. 92 to93.6 C.

The fumarate salt thereof, M.P. 100112 C. (doc), is prepared inconventional manner by neutralizing the free base with furnaric acid inmethanol and recrystallizing the product from methanol at C.

The hydrochloride salt thereof, M.P. 158-159 C., is prepared inconventional manner by reacting the free base with hydrogen chloride inethanol and recrystallizing the product from ethanol.

The methiodide salt thereof, M.P. 166-l67 C., is prepared inconventional manner by treating the base with an excess of methyl iodideand recrystallizing the resulting product from ethanol.

The methobromide salt thereof, M.P. 195197 C., is prepared inconventional manner by treating a solution of the base in methylenechloride, at 0 C., with an excess of gaseous methyl bromide andrecrystallizing the product from ethanol.

EXAMPLE 3 Bis-(p-chlorophenoxy)acetic acid fi-morpholinoethyl esteronoooornom N o A mixture of 15.8 g. (0.12 mole) of 4-(6-hydroxyethyl)morpholine in 100 ml. of toluene is cooled to about 5 C. in an ice-saltbath. To the cooled mixture is then added dropwise with stirring asolution of g. (0.06 mole) of bis-(p-chlorophenoxy) acetyl chloride in50 ml. of toluene, While maintaining the temperature of the reactionmixture between 5 C. to 0 C. with external cooling. After the additionis completed, the mixture is stirred for an additional ten minutes andthen 50 ml. of ice-water and 75 ml. of an aqueous sodium bicarbonatesolution are added and the phases separated. The organic phase is thenwashed three times with 100 ml. (each) of water, then dried overmagnesium sulfate and evaporated. The residue thus obtained isrecrystallized from cyclohexane, using some charcoal to remove coloredby-products, to obtain bis-(pchlorophenoxy) acetic acidB-morpholinoethyl ester, M.P. 75 to 76.5 C.

1 2 EXAMPLE 4 Bis-(p-chlorophenoxy)acetic acid l-[B-(p-chlorophenoxy)ethyl] -4-piperidyl ester Step A. Preparation of4-hydroxy-l-[fl-(p-chlorophenoxy)ethyl]piperidine: A mixture of 30.45 g.(0.3 mole of 4-hydroxypiperidine, 20.6 g. (0.15 mole) of anhydrous p0-tassium carbonate, 5 g. of potassium iodide and 300 ml. of methanol isheated to reflux on a water bath and then treated with a solution of g.(0.15 mole) of [ET-(pchlorophenoxy)-ethyl bromide in 100 ml. ofmethanol. The resulting mixture is then refluxed for 64 hours, filteredand the filtrate evaporated. To the solid residue thus obtained is added100 ml. of petroleum ether. The resulting mixture is then filtered andthe solid material suspended in 700 ml. of distilled water. Theinsoluble material is then filtered ofi", dissolved in 400 ml. ofchloroform and the resulting solution dried over magnesium sulfate andevaporated. The residue is recrystallized from 250 ml. of hexane and 80ml. of ethyl acetate and filtered, with the aid of charcoal, throughCelite to obtain 4-hydroxy-l-[ 8- (p-chlorophenoxy)ethyljpiperidine,M.P. 111-112 C.

Step B. Preparation of bis-(p-chlorophenoxy)acetic acid 1[B-(p-chlorophenoxy)ethyl] 4-piperidyl ester: To a solution of 11.2 g.(0.0438 mole) of 4-hydroxy-l-[fi-(pchlorophenoxy)ethyl]piperidine in1400 ml. of dry toluene is added 4.5 g. (0.044 mole) of triethylamine.The resulting mixture is stirred at room temperature and then there isadded thereto, dropwise, a solution of 19 g. (0.057 mole) ofbis-(p-chlorophenoxy)acety1 chloride in ml. of toluene. The resultingmixture is then stirred overnight at room temperature, filtered and thefiltrate extracted three times with 100 ml. (each) of cold 10% aqueoussodium bicarbonate solution and then washed three times with 100 ml.(each) of water and the organic phase evaporated to obtainbis-(p-chlorophenoxy)acetic acid 1-[/3-(p-chlor0phenoxy)ethyl]-4-piperidyl ester, M.P. 106.5- 107 C.

EXAMPLE 5 Bis-(p-chlorophenoxy)acetic acid l-propargyl-4-piperidyl esterStep A. Preparation of 4 hydroxy-l-propargylpiperidine: A mixture of35.4 g. (0.35 mole) of 4-hydroxypiperidine, 5 g. of potassium iodide,24.4 g. of (0.175 mole) of anhydrous potassium carbonate and 300 ml. ofmethanol is heated to reflux on a water bath and then treated dropwisewith a solution of 41.7 g. (0.35 mole) propargyl bromide in ml. ofmethanol. The resulting mixture is then refluxed overnight, filtered andthe filtrate evaporated. The residue thus obtain is recrystallized threetimes from ethyl acetate (using charcoal as an aid) to obtain 4 hydroxyl-propargylpiperidine, M.P. 102.5- 103.5 C.

Step B. Preparation of his (p-chlorophenoxy)acetic acid1-propargyl-4-piperidyl ester: To a solution of 11.5 g. of4-hydr0xy-l-propargylpiperidine in 1200 m1. of anhydrous diethyl etheris added, dropwise and at room temperature, a solution of 29 g. ofbis-(p-chlorophenoxy) acetyl chloride in 60 ml. of anhydrous diethylether. The resulting mixture is stirred overnight at room temperatureand then several small pieces of ice and ml. of 2 N sodium carbonate areadded with stirring. The organic phase is separated, Washed three timeswith ml. (each) of a saturated sodium chloride solution, dried overmagnesium sulfate and evaporated. The resulting viscous oil is dissolvedin a minimum amount of chloroform and the resulting solution passedthrough silica gel and the silica gel then eluted first with 1 liter ofpetroleum ether, then with 1 liter of isopropyl ether and finally with 1liter of benzene. The solvents are then evaporated off and the residuesdissolved in anhydrous diethyl ether. Hydrogen chloride gas is bubbledthrough the ether solution and the resulting solid material filtered otfand recrystallized from ethyl acetate (employing charcoal as an aid) toobtain hygroscopic bis-(p-chlorophenoxy) acetic acidl-propargyl-4-piperidyl ester hydrochloride, M.P. 115.5118 C.

EXAMPLE 6 Bis-(p-chlorophenoxy)acetic acid Z-dimethylamino-Z-methylpropyl ester CH3 CH3 A mixture of 23.4 g. (0.2 mole) of2-dimethylamino-2- methylpropanol-l and 100 ml. of toluene is cooled toC. and then there is added thereto, dropwise with stirring, a solutionof 33.15 g. of 0.1 mole) of bis-(p-chlorophenoxy)acetyl chloride in 40ml. of toluene. After the addition is completed the mixture is stirredfor an additional /2 hour, filtered and the filtrate extracted twicewith 100 ml. (each) of a aqueous solution of sodium bicarbonate. Theorganic phase is then washed three times with 100 ml. (each) of water,dried over potassium carbonate and evaporated. The residue is dissolvedin anhydrous diethyl ether and hydrogen chloride gas is bubbled throughthe ether solution. The solid material thus obtained is filtered OE andrecrystallized from 300 ml. of ethyl acetate (employing charcoal as anaid) to obtain bis-(pchlorophenoxy)acetic acid 2dimethylamino-Z-methylpropyl ester hydrochloride, M.P. 148-148.5 C.

EXAMPLE 7 /CHC O O CHzCHzCH2-N Cl CH:

A mixture of 20.6 g. (0.2 mole) of 3-dimethylaminopropanol-l in 100 ml.of toluene is cooled to 0 C. and there is added thereto, dropwise withstirring, a solution of 33.15 g. (0.1 mole) ofbis-(p-chlorophenoxy)acetyl chloride in ml. of toluene. After theaddition is completed the reaction temperature is allowed to rise toroom temperature and the mixture stirred for an additional 2 hours. Themixture is then filtered, the filtrate treated twice with 100 ml. (each)of cold 10% aqueous sodium bicarbonate, washed three times with 100 ml.(each) of a saturated aqueous sodium chloride solution and then driedover potassium carbonate and evaporated. The residue is dissolved inanhydrous diethyl ether and hydrogen chloride gas bubbled through theether solution. The solid material thus obtained is filtered oil andrecrystallized twice from 750 ml. (each) of ethyl acetate (employingcharcoal as an aid) to obtain bis-(p-chlorophenoxy) acetic acid'y-dimethylaminopropyl ester hydrochloride, M.P. 131.7132 C.

Bis-(p chlorophenoxy)acetic acid methyl ester, 10 grams, is mixed with10 grams of S-anilinoethanol, 50 mg.

of sodium methoxide and 10 ml. of toluene. The result-- ing mixture isslowly heated to distill very slowly through a Vigreux column. When thetemperature at the distilling head reaches C., the reaction mixture iscooled to 65 C. and then evaporated on a rotary evaporator employing 12mm. vacuum and maintaining the temperature between 6570 C. The crudeproduct is chromatographed on a silica gel column and the productrecovered by wash-' ing the column With benzene. The benzene is thenevaporated off to obtain bis-(p-chlorophenoxy)acetic acid ,8-anilinoethyl ester, M.P. 9196 C.

EXAMPLE 9 Bis-'(p-chlorophenoxy)acetic acid fi-pyrrolidinoethyl esteroHoooomom-N To a mixture of 122 g. (0.313 mole) ofbis-(p-chlorophenoxy)acetic acid methyl ester, 50 g. (0.435 mole) ofl-(B-hydroxyethyl) pyrrolidine and 200 ml. of benzene is added withstirring 1 g. of sodium methoxide. The resulting mixture is heated at100 C. for 1 hour and then cooled to about 15-20 C. To the cooledmixture is added 500 ml. of benzene and 500 ml. of water. The aqueousphase is then extracted with 500 ml. of benzene and the combined organiclayers washed twice with 500 ml. (each) of water and then evaporated ona rotary evaporator. The residue is dissolved in 200 ml. of isopropauol.To the cooled alcohol solution (5 C.) is added, with stirring, asolution of 11% hydrochloric acid in isopropanol until the pH thereofis 1. The resulting mixture is filtered, the filtrate cooled overnightat -5 C. The resulting solid material is filtered off and then slurriedat reflux with 50 ml. ligroin. The solids are recovered by filtration,then slurried at 20 C. with 100 g. of carbon tetrachloride and filteredoff to obtain bis-(p-chlorophenoxy)acetic acid fi-pyrrolidinoethyl esterhydrochloride, M.P. -130 C.

EXAMPLE 10 Bis-(p-chlorophenoxy)acetic acid l-benzyl-4-piperidyl ester f/CH0 0 0 CH2- To a mixture of 38 g. (0.2 mole) of1-benzyl-4-hydroxypiperidine, 22 g. (0.22 mole) of triethylamine and 100ml. of toluene is added, while stirring and maintaining the reactiontemperature at about 20-25 C., a solution of 66 g. (0.2 mole) ofbis-(p-chlorophenoxy)acetyl chloride in 200 ml. of toluene. Theresulting mixture is stirred for an additional 2 hours at 25 C. and thencooled to 5 C. To the cooled mixture is added 500 ml. of water. Theaqueous phase is extracted with 500 ml. of benzene and the combinedorganic layers are then Washed successively with 500 ml. of 1 Nhydrochloric acid, 1 liter of water, 200 ml. of 5% aqueous sodiumbicarbonate solution and then dried over magnesium sulfate andevaporated on a rotary evaporator at 100 mm. vacuum. The residue thusobtained is crystallized from 300 m1. of

methanol and then recrystallized from 500 ml. of methanol to obtainhygroscopic bis-(p-chlorophenoxy)acetic acid 1-benzyl-4-piperidyl ester,M.P. 4749 C.

EXAMPLE ll Bis-(p-chlorophenoxy) acetic acid {3-( 1-methyl-2- ethylester To a mixture of 163 g. (0.5 mole) of bis-(p-chlorophenoxy)aceticacid methyl ester, 83 g. (0.5 mole) of N-ethyl-N-phenylethanolamine and1000 ml. of toluene is added, with stirring 2 g. of sodium methoxide.The resulting mixture is heated at 120 C. for 1 hour and then cooled toabout 20 C. To the cooled mixture is added 500 ml. of benzene and 500ml. of water. The resulting mixture is stirred for 15 minutes, theorganic phase separated and washed twice with 500 ml. (each) of Waterand then evaporated on a rotary evaporator at 100 mm. vacuum. Theresidue is dissolved in 500 ml. of isopropanol and the resultingsolution cooled to 5 C., filtered and the solids washed with 200 ml. ofcold isopropanol. The washed solids are dissolved in 500 m1. ofisopropanol and the resulting solution treated at reflux wtih 10 g. ofcharcoal, then cooled and filtered. The filtrate is allowed to stand fortwo weeks at room temperature. The resulting crystalline material isrecovered by decanting olf the solvent, then ground in a mortar andslurried at room temperature with 500 ml. of isopropanol. The resultingmixture is filtered and the solids washed with 200 ml. of isopropanol toobtain bis-(p-chlorophenoxy)acetic acid {3-(N-ethylanilino) ethyl ester,M.P. 56- 60 C.

EXAMPLE l2 Bis- (p-chlorophenoxy acetic acid [3- 1-methyl-2-pyrrolidinyl)ether ester To a mixture of 2.50 g. (0.022 mole) ofl-l-methyl-Z- (fi-hydroxyethyl)pyrrolidine, 2.50 g. (0.025 mole) oftriethylamine and 10 ml. of toluene, cooled to C., is added dropwise 55ml. of a toluene solution containing 0.03 mole ofbis-(p-chlorophenoxy)acetyl chloride at a rate such that the reactiontemperature does not exceed about 5 C. After the addition is completed,the mixture is stirred overnight at 20 C., then 50 ml. of chloroform isadded and the resulting mixtures extracted with 50 ml. of aqueous sodiumcarbonate solution. The organic phase is dried over potassium carbonateand evaporated to obtain l-bis-(p-chlorophenoxy)acetic acidfi-(l-methyl-Z- pyrrolidinyl)ethyl ester as a viscous oil.

The fumarate salt thereof, M.P. 149-150.? C., is obtaned by treating theoily base with a methanolic solution of fumaric acid, precipitating thesalt by the addition of diethyl ether and recrystallizing the thusobtained salt from methanol-diethyl ether (1:1).

EXAMPLE l3 Bis(p-chlorophenoxy)acetic acid 1-phenyl-4-piperidyl To amixture of 8.80 g. (0.05 mole) of 1-phenyl-4- hydroxypiperidine, 6.0 g.(0.06 mole) of triethylamine and 20 ml. of toluene, cooled to 0 C., isadded dropwise 50 ml. of a toluene solution containing 0.06 mole of bis-(p-chlorophenoxy)acetyl chloride at such a rate that the reactiontemperature does not exceed about 5 C. After the addition is completed,the mixture is stirred overnight at 20 C., then 300 ml. of chloroform isadded and the resulting mixture extracted twice with ml. (each) of 10%aqueous sodium carbonate solution. The organic phase is dried overpotassium carbonate and evaporated. The residue is crystallized fromacetone at -5 C. to obtain bis-(p-chlorophenoxy)acetic acidl-pheny-4-piperidyl ester, M.P. 117-119.5 C.

EXAMPLE 14- Bis-(p-chlorophenoxy)acetic acid S-quinuclidinyl ester To 20ml. of methylene chloride containing 3.80 g. (0.03 mole) of3-quinuclidinol is added 3.50 g. of triethylamine and 10 ml. ofmethylene chloride containing 10.0 g. of bis-(p-chlorophenoxy)acetalchloride while maintaining the reaction temperature between 0 and 5 C.The mixture is then stirred overnight at room temperature, then 300 ml.of chloroform is added and the resulting mixture extracted twice with100 ml. (each) of,

10% aqueous sodium carbonate solution. The organic phase is dried overpotassium carbonate and evaporated. The residue is crystallized frombenzene/c-hexane(1:l) to obtain bis-(p-chlorophenoxy)acetic acid3-quinuclidinyl ester, M.P. 114-115 C.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformula CHCOOR Cl O and the non-toxic addition and quaternary saltsthereof,

wherein R represents 4. The compound of claim 1 which isbis-(p-chlorophenoxy)acetic acid 1-propargy1-4-piperidyl ester.

5. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid1-benzyl-4-piperidyl ester.

6. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid1-pheny1-4-piperidyl ester.

7. The compound of claim 1 which is bis-(p-chlorophenoxy)acetic acid3-quinuclidiny1 ester.

No references cited.

US. Cl. X.R.

